This is the first resubmission of a competing renewal for the research grant R01 DA15214, a five-year project that activated on 07 February 2003. During the current funding period, our work focused on delineating the neuronal circuitry and associated neurotransmitter systems underlying cocaine priming-induced reinstatement of cocaine seeking and, to a lesser extent, cocaine reinforcement. Our work indicates that D1-like and D2 dopamine receptors in the shell, but not core, subregion of the nucleus accumbens play critical roles in the reinstatement of cocaine seeking and cocaine reinforcement. In addition, we demonstrated that administration of cocaine directly into the medial prefrontal cortex (mPFC) reinstates cocaine-seeking behavior by increasing AMPA-mediated glutamate transmission in the nucleus accumbens. Our research, combined with that of others, demonstrates that a collection of limbic nuclei, including the ventral tegmental area (VTA), nucleus accumbens, mPFC, amygdala, hippocampus and ventral pallidum, underlie cocaine reinforcement and the reinstatement of cocaine seeking. In Specific Aims 1 and 2 of the present application, we extend this circuitry to include the pedunculopontine tegmental nucleus (PPTg), which receives glutamatergic inputs from the mPFC and sends glutamatergic and cholinergic projections to the VTA that synapse on dopaminergic neurons. The overarching hypothesis of these experiments is that the serial circuit encompassing the mPFC, PPTg, VTA and nucleus accumbens is critically involved in cocaine reinforcement as well as cocaine priming-induced reinstatement of drug seeking. We also propose to examine a practical application for the emerging neuronal circuitry underlying cocaine reinforcement and reinstatement. Thus, in Specific Aim 3 we will assess the effect of reversible inactivation of various limbic nuclei on cocaine reinforcement and reinstatement of cocaine seeking. The novel aspect of this aim is the method of neuronal inactivation. We will utilize deep brain stimulation (DBS), a technique increasingly used clinically for the treatment of neurological diseases that has recently been tested as a potential treatment for a range of psychiatric disorders as well. Cocaine addiction remains a major public health issue in the United Sates. The experiments described in this grant application are designed to delineate the neuronal circuitry and associated neurotransmitter systems underlying influenced by cocaine using animal models. The overarching goal of this project is to identify novel therapeutic targets for cocaine craving and addiction.